Tuberculosis (TB) is a serious public health issue and rational development of effective vaccines requires that we understand the cellular mechanisms mediating protective immunity; this is the focus of the current proposal. We show here that while protective memory can be effective against Mycobacterium tuberculosis (Mtb) it is delayed when the challenge route mimics natural exposure. Crucially, this delay allows bacterial growth in the lungs even of vaccinated mice. Clearly, accelerating the memory response to result in earlier suppression of bacterial growth is an important goal. In this regard we have identified a novel population of memory cells that produces interleukin (IL)-17, resides in the lung, responds quickly to aerosol infection and which is required for protective memory. In the absence of this IL-17 memory population, the interferon (IFN)-? memory response is lost. The IL-17-producing memory cells are IL-23 dependent and are associated with an accelerated chemokine response. These data prompted the hypothesis that IL-17-producing memory cells recruit IFN-? producing memory cells. If this is true then the IL-17-producing memory population is a novel prime target for vaccination. Specifically, manipulating the response of these cells could overcome the delay in the protective memory that limits the efficacy of current vaccine strategies. In this proposal we will test the following working model: Vaccine-induced, IL-23 dependent, IL-17-producing memory CD4+ T cells resident in the lung respond to Mtb, produce IL-17, trigger the local expression of chemokines which attract IFN-?-producing memory CD4+ T cells. These IFN-? memory CD4+ T cells then activate myeloid cells to halt Mtb growth. The model will be tested using three aims: Aim One: To determine the factors required for induction of protective memory T cells. The requirement for IL-23 in proliferation, survival and phenotypic development of IL-17-producing memory cells capable of populating the lung will be determined. Aim Two: To determine whether IL-17 mediates vaccine-induced protection by recruiting IFN-? producing CD4+ T cells. We will determine whether IL-17-induced chemokine responses and accelerated accumulation of IFN-?-producing memory cells are essential for vaccine-induced protection. Aim Three: To determine whether modulating the IL-17 memory response in the lung can increase protection. We will determine whether increasing the IL-17 population in the lung improves vaccine-induced protection. Proof of this working model will provide a basis for rational vaccine design and investigation of the role of these cells in humans. PUBLIC HEALTH RELEVANCE: We know too little about how the vaccine-induced protective response to tuberculosis works. If we do not know how the response works it is difficult to improve upon it. By investigating the way the response works we have identified new cell types that can be targeted by vaccination. These new cell types may improve the protective effect of vaccines and thereby reduce the incidence of tuberculosis in the world. This will have a significant impact in worldwide public health.